Flumazenil in the treatment of cirrhotic patients with hepatic encephalopathy : a randomized double-blind clinical trial

Abstract

Objective : To assess the therapeutic effectiveness of flumazenil, a specific central benzodiazepine (Bz) receptor antagonist, in terms of the fast improvement of clinical stage of mental status of cirrhotic patients with hepatic encephalopathy (HE) and the impact of that drug on the changes of these patients. Design : A randomized double-blind clinical trial. Setting : Zhong Shan Hospital, a tertiary care hospital affiliated with Shanghai Medical University, Shanghai, China. Patients : Twenty-five consecutive cirrhotic patients with HE of clinical stage clinical stage of 2 to 4 (Conn’s 5-stage grading), diagnosed by clinical, psychometric, biochemical biochemical and/or histological evidences without history of recently using Bz, were randomly assigned in the treatment (trt, n=13) or control group (ctrl grp, n=12). Interventions : Patients received flumazenil (1.0 mg bolus intravenous) or placebo (normal saline) respectively in trt grp or ctrl grp during the intensive observation period (IOP, 1.5 hours) and were followed up until discharge or death in ward. All patients received accompanied conventional therapy for HE since the commencement of the trial. Results : There was no significant difference (p=0.124,power=56%) between the 2 groups in terms of the effective responders, defined as the improvement of clinical stage of HE up to and maintenance in Grade 0 or 1 during IOP (3 in trt grp while 0 in ctrl grp). However, 8 patients in trt grp showed favorably positive responses of clinical stage of HE comparing with 1 in ctrl grp (p=0.008). These positive responses were not related with the baseline HE stages or liver functions. Most of the positive changes initiated within 20 minutes and, however, did not maintain stable during the whole IOP. Most patients regained their normal mental function in the 2nd to 5th day of the trial. There was no statistical difference of the death rate between 2 groups (3 in trt grp and 5 in ctrl grp). Conclusion : Comparing with placebo, flumazenil could not effectively improve the clinical stage of HE, but could induce fast but unstable positive response in about 63% cirrhotic patients. The application of flumazenil should be considered of its clinical significance in the perspective of the family members.